Nod2 在 T 细胞内在性保护中抵抗 Th17 介导的葡萄膜炎的作用。
T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis.
机构信息
VA Portland Health Care System, Portland, OR, 97239, USA.
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, 97239, USA.
出版信息
Nat Commun. 2020 Oct 26;11(1):5406. doi: 10.1038/s41467-020-18961-0.
Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2 CD4 T cells or retina-specific autoreactive CD4 T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4 T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4 T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.
核苷酸结合寡聚化结构域蛋白 2（NOD2）的突变可引起 Blau 综合征，这是一种以葡萄膜炎为特征的炎症性疾病。Nod2 的抗菌功能已得到充分证实，但调控异常的 Nod2 导致葡萄膜炎的细胞机制尚不清楚。在这里，我们报告了 Nod2 在抑制 Th17 免疫和实验性葡萄膜炎中的一种非传统的、T 细胞内在的功能。用 Nod2 CD4 T 细胞或缺乏 Nod2 的视网膜特异性自身反应性 CD4 T 细胞重建淋巴减少宿主，揭示了 Nod2 在葡萄膜炎中的一种 T 细胞自主、Rip2 独立的机制。在未成熟的动物中，Nod2 在 TCR 连接的下游起作用，以抑制与涉及 IL-17 和 Ccr7 的自身反应样特征相关的记忆 CD4 T 细胞的激活。有趣的是，两名 Blau 综合征患者的 CD4 T 细胞显示出升高的 IL-17 和增加的 CCR7。我们的数据将 Nod2 定义为 Th17 免疫的 T 细胞内在变阻器，并为基于 T 细胞的治疗 Nod2 相关疾病（如 Blau 综合征）开辟了新途径。
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